Final Report Summary - ELIMINATESENESCENT (The Role of Elimination of Senescent Cells in Cancer Development)
Cellular senescence, which is a terminal cell cycle arrest, is a potent tumor suppressor mechanism that limits cancer initiation and progression; it also limits tissue damage response and aids embryonic development. While senescence is protective in the cell autonomous manner, senescent cells secrete a variety of factors that lead to inflammation, tissue destruction and promote tumorigenesis and metastasis in the sites of their presence. We proposed to eliminate senescent cells from tissues in order to prevent the deleterious cell non-autonomous effects of these cells. We discovered the mechanisms of interaction of senescent cells with NK cells and other immune cells and tested harnessing these mechanisms for elimination of senescent cells. We also discovered two pathways that regulate the viability of senescent cells in the cell-autonomous manner. The molecular players identified by these approaches were readily implemented for the elimination of senescent cells in vivo. Elimination of senescent cells using pharmacological and genetic approaches affects stem cells in the micro-environment of senescent cells. We have evaluated the impact of the elimination of senescent cells on tumor progression, in mouse models, where these cells are present during initial stages of tumorigenesis. Additionally, we developed a methodology that allowed quantitative identification of senescent cells from in vivo models. The ability to eliminate senescent cells will eventually lead to novel ways of cancer prevention and treatment, by elimination of senescent cells from the sights of tissue damage, pre-malignant lesions and tumors following therapy. Such approaches might also extend healthspan.